Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8873
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DC Field | Value | Language |
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dc.contributor.author | Barthels, Fabian | - |
dc.contributor.author | Meyr, Jessica | - |
dc.contributor.author | Hammerschmidt, Stefan J. | - |
dc.contributor.author | Marciniak, Tessa | - |
dc.contributor.author | Räder, Hans-Joachim | - |
dc.contributor.author | Ziebuhr, Wilma | - |
dc.contributor.author | Engels, Bernd | - |
dc.contributor.author | Schirmeister, Tanja | - |
dc.date.accessioned | 2023-03-02T11:02:25Z | - |
dc.date.available | 2023-03-02T11:02:25Z | - |
dc.date.issued | 2021 | - |
dc.identifier.uri | https://openscience.ub.uni-mainz.de/handle/20.500.12030/8889 | - |
dc.description.abstract | Staphylococcus aureus is one of the most frequent causes of nosocomial and community-acquired infections, with emerging multiresistant isolates causing a significant burden to public health systems. We identified 2-sulfonylpyrimidines as a new class of potent inhibitors against S. aureus sortase A acting by covalent modification of the active site cysteine 184. Series of derivatives were synthesized to derive structure-activity relationship (SAR) with the most potent compounds displaying low micromolar KI values. Studies on the inhibition selectivity of homologous cysteine proteases showed that 2-sulfonylpyrimidines reacted efficiently with protonated cysteine residues as found in sortase A, though surprisingly, no reaction occurred with the more nucleophilic cysteine residue from imidazolinium-thiolate dyads of cathepsin-like proteases. By means of enzymatic and chemical kinetics as well as quantum chemical calculations, it could be rationalized that the SNAr reaction between protonated cysteine residues and 2-sulfonylpyrimidines proceeds in a concerted fashion, and the mechanism involves a ternary transition state with a conjugated base. Molecular docking and enzyme inhibition at variable pH values allowed us to hypothesize that in sortase A this base is represented by the catalytic histidine 120, which could be substantiated by QM model calculation with 4-methylimidazole as histidine analog. | en_GB |
dc.language.iso | eng | de |
dc.rights | CC BY | * |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | * |
dc.subject.ddc | 570 Biowissenschaften | de_DE |
dc.subject.ddc | 570 Life sciences | en_GB |
dc.subject.ddc | 610 Medizin | de_DE |
dc.subject.ddc | 610 Medical sciences | en_GB |
dc.title | 2-sulfonylpyrimidines as privileged warheads for the development of S. aureus sortase A inhibitors | en_GB |
dc.type | Zeitschriftenaufsatz | de |
dc.identifier.doi | http://doi.org/10.25358/openscience-8873 | - |
jgu.type.dinitype | article | en_GB |
jgu.type.version | Published version | de |
jgu.type.resource | Text | de |
jgu.organisation.department | FB 09 Chemie, Pharmazie u. Geowissensch. | de |
jgu.organisation.number | 7950 | - |
jgu.organisation.name | Johannes Gutenberg-Universität Mainz | - |
jgu.rights.accessrights | openAccess | - |
jgu.journal.title | Frontiers in molecular biosciences | de |
jgu.journal.volume | 8 | de |
jgu.pages.alternative | 804970 | de |
jgu.publisher.year | 2021 | - |
jgu.publisher.name | Frontiers | de |
jgu.publisher.place | Lausanne | de |
jgu.publisher.issn | 2296-889X | de |
jgu.organisation.place | Mainz | - |
jgu.subject.ddccode | 570 | de |
jgu.subject.ddccode | 610 | de |
jgu.publisher.doi | 10.3389/fmolb.2021.804970 | de |
jgu.organisation.ror | https://ror.org/023b0x485 | - |
Appears in collections: | JGU-Publikationen |
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